These continuation studies focus on large pancreas transplant alone (PTA), kidney transplant alone (KTA), and P after K (PAK) transplant populations of type 1 diabetic (D) patients (pts)in order to better understand diabetic nephropathy (DN), the leading cause of renal failure and calcineurin inhibitor toxicity (CNIT). Objectives are: (a) to determine whether PTA can more readily arrest or reverse the early vs. the more established lesions of DN; (b) to continue studies of renal structural-functional relationships in DN, with emphasis on the multifaceted pathologic DN lesions, including glomerular (G),vascular, interstitial (Int) lesions and glomerular-tubular junction abnormalities (GTJA) including atubular glomeruli (AG) and the reversibility of these lesions by PTA; (c) to continue studies of DN natural history and the role of renal biopsy in predicting outcome; (d) to elucidate G podocyte and endothelial cell abnormalities in DN and their reversibility by PTA; (e) to study the recurrence of DN in the KTA; (f) to study the molecular/genetic basis of DN and develop cellular markers of DN risk; (g) to determine the long-term structural and functional consequences of calcineurin inhibitors (CNI)on the native kidneys of PTA recipients; and (h) to determine the shorter-term (5 yr) consequences on the native kidneys of PTA recipients in order to more fully describe the pathology, compare cyclosporine to Prograf injury, and elucidate reversibility of these lesions with CNI dose reduction or discontinuation. Together, these studies will help to elucidate the pathogenesis and natural history of DN, unravel some of the molecular and genetic aspects of this disease, describe the dynamics of DN reversal in PTA and PAK pts,and recurrence in KTA pts and expand our knowledge of the nephrotoxic effects of CNIs. RELEVANCE (See instructions): Diabetes is the single most important cause of kidney failure, responsible for more than 45% of all new cases in the USA. Certain drugs [calcineurin inhibitors (CNI)] used for prevention of rejection of transplanted organs cause kidney failure in as many as 20% of recipients. These studies will help to understand how diabetes and these drugs destroys the kidney and define the possibilities for healing of these injuries.